On the in vivo significance of bacterial resistance to antimicrobial peptides

Abstract

Antimicrobial peptides (AMPs) are at the front-line of host defense during infection and play critical roles both in reducing the microbial load early during infection and in linking innate to adaptive immunity. However, successful pathogens have developed mechanisms to resist AMPs. Although considerable progress has been made in elucidating AMP-resistance mechanisms of pathogenic bacteria in vitro, less is known regarding the in vivo significance of such resistance. Nevertheless, progress has been made in this area, largely by using murine models and, in two instances, human models of infection. Herein, we review progress on the use of in vivo infection models in AMP research and discuss the AMP resistance mechanisms that have been established by in vivo studies to contribute to microbial infection. We posit that in vivo infection models are essential tools for investigators to understand the significance to pathogenesis of genetic changes that impact levels of bacterial susceptibility to AMPs. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides.

Keywords: Antimicrobial peptides; Cell envelope modifications; In vivo models; Pathogenesis; Resistance mechanisms; Transporters.

Fig. 1. The Sap transporter contributes to virulence of H. ducreyi in human volunteers

(A) Arms of volunteer # 390 at Day 6 post-inoculation with parent strain 35000HP (left panel) or mutant strain 35000HPsapBC (right panel) [79]. Arrows indicate sites of inoculation (outlined by black dots in right panel). Pustules formed at all parent-inoculated sites (left) but no mutant-inoculated sites (right) in this volunteer. Stickers on volunteer arms in photos indicate scale in cm, volunteer # (390), arm depicted (R, right arm; L, left arm), and date of photograph. (B) Pustule formation rates in human volunteers inoculated with parent strain 35000HP and either 35000HPsapA [13] or 35000HPsapBC [79]. For the mutants, the degree of attenuation in vivo correlated with the level of LL-37 resistance in vitro [79]. Asterisks indicate significant differences from parent strain in each trial (P < 0.05). Photographs courtesy of Stanley M. Spinola.